It is a common problem for human beings to overcome cancer. For the purpose, many anti-cancer agents have been developed until now, but the expression of multidrug resistance of cancer has become a clinical problem. Multidrug resistance is a phenomenon (cross-resistance) in which cancer cells resist to not only the particular anti-cancer agent administered, but also the other anti-cancer agents, due to an administration of an anti-cancer agent or a resistance of cancer cells by nature to anti-cancer agents. Reportedly, about 50% of patients newly diagnosed as cancer showed a drug resistance in the treatment of cancer, and more than 90% of the deaths showed some behaviors associated with the resistance of cancer cells to anti-cancer agents during the treatment with anti-cancer agents. Therefore, it has become extremely important in cancer chemotherapy to overcome multidrug resistance to anti-cancer agents of cancer cells.
Although a mechanism of cancer cells causing multidrug resistance has not been clearly elucidated, it is considered to result from a reduced concentration of anti-cancer agents in the cells when said cells have acquired multidrug resistance. On the other hand, many cancer cells having multidrug resistance produce P-glycoprotein excessively and this P-glycoprotein may play a role in transporting anti-cancer agents out of the cells. P-glycoprotein is coded by a gene called MDR1 on human being. Thus the over-expression of MDRI gene in human cancer cells is considered to be a cause of acquiring resistance (MDR1 resistance). P-glycoprotein has low substrate specificity and can bind with various kinds of compounds to transport drugs out of the cells. It follows that once P-glycoprotein expresses in cancer cells, the cells will acquire resistance to many other anti-cancer agents. In fact, it is known that many structurally different anti-cancer agents such as adriamycin, vinblastine, vincristine, actinomycin D, colchicine become a substrate for transporting outside cells by P-glycoprotein. Therefore, it is considered that inhibiting the function of P-glycoprotein will lead to overcoming multidrug resistance. It is reported that about 30% of multidrug resistances is caused by P-glycoprotein.
It is known that messenger RNA of MDR1 gene encoding P-glycoprotein expresses in normal tissue, for example, kidney, adrenal, large intestine, small intestine, intestinum colon, lung, liver, pancreas, or lymphocyte. In kidney P-glycoprotein plays a part to transport drugs out of the body. The reason why anti-cancer agents have low activity in kidney cancer where kidney cells were cancerous is that P-glycoprotein produced therein will transport anti-cancer agents outside the cells. Recently, it is found that the main substance of blood brain barrier which controls transport of drugs into the brain is P-glycoprotein. This means that the concentration of anti-cancer agents delivered into brain, kidney, adrenal, large intestine, small intestine, intestinum colon, lung, liver, pancreas, lymphocyte of leukemia, etc., can be increased by inhibiting P-glycoprotein. Thus, P-glycoprotein inhibitors are expected to enhance effect of anti-cancer agents on brain tumor, kidney cancer, adrenal cancer, large intestine cancer, small intestine cancer, intestinum colon cancer, lung cancer, liver cancer, pancreas cancer, or leukemia, etc.
In the field of cancer chemotherapy, many anti-cancer agents have been used such as mitomycin, cyclophosphamide, melphalan, nimustine, carboquone, vincristine, vinblastine, vindesine, bleomycin, 5-fluorouracil, adriamycin, cisplatin, actinomycin D, methotrexate, aclarubicin, toyomycin, neocarzinostatin, ifosfamide, etoposide, camptothecin, doxorubicin, irinotecan. Those drugs have characteristic anti-cancer spectra. Some of those anti-cancer agents are known to bring about a resistance of cancer cells to the agents by continuous or a long term administration. Further, the problem of cross-resistance has arisen. Therefore it has been required to activate or enhance the sensitivity of cancer cells having resistance to anti-cancer agents in the field of cancer chemotherapy.
Taxol and its derivative taxotere were approved in U.S.A. in recent years, and will be done in Japan. They are expected to be one of the leading drugs of solid carcinoma chemotherapy in the future, because of having a potent and strong anti-cancer activity, particularly in the field of solid carcinoma. However, taxol is known to be a substrate for transporting outside cells by P-glycoprotein, and its activity may be weakened by MDRl resistance. Recently, it is reported that P-glycoprotein inhibitors can overcome taxol resistance in MDR1 resistance cells (Cancer Res. vol. 55, 1086-1091, 1995). This shows that P-glycoprotein inhibitors are also effective for taxol resistance.
Some of the instant compounds are included in a series of isoprenylamine derivatives having anti-viral and anti-tumor activities disclosed in Japanese Patent Kokoku 1-36457 in which there is no reference that the isoprenylamine derivatives have the function as multidrug resistance inhibitors for overcoming multidrug resistance of cancer.
Tsuruo et al. report that verapamil represented by the following formula (III) ##STR3## inhibits P-glycoprotein and overcomes MDR1 resistance (Cancer Res., vol. 41, 1967-1972, 1981).
Nakagawa et al., Japanese Patent Kokoku 5-16411 discloses a compound of formula (IV) ##STR4## and the pharmaceutically acceptable salts thereof, which have an activity of overcoming adriamycin (ADM) resistance to ADM, one of anti-cancer drugs. Ogawa et al, Japanese Patent Kokai 2-138211, discloses that the malate of formula (IV) has an activity of enhancing the anti-cancer activity.
There is no report that the compound of formula (IV) enhances an anti-cancer activity of taxol in MDR1 resistance cells.